Download Increased risk of Alzheimer`s disease in Type II diabetes: insulin

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Increased risk of Alzheimer’s disease in Type II
diabetes: insulin resistance of the brain or
insulin-induced amyloid pathology?
G.J. Biessels1 and L.J. Kappelle2
Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center, Utrecht, The Netherlands
Abstract
Type II diabetes mellitus (DM2) is associated with an increased risk of cognitive dysfunction and dementia.
The increased risk of dementia concerns both Alzheimer’s disease and vascular dementia. Although some
uncertainty remains into the exact pathogenesis, several mechanisms through which DM2 may affect the
brain have now been identified. First, factors related to the ‘metabolic syndrome’, a cluster of metabolic and
vascular risk factors (e.g. dyslipidaemia and hypertension) that is closely linked to DM2, may be involved.
A number of these risk factors are predictors of cerebrovascular disease, accelerated cognitive decline and
dementia. Secondly, hyperglycaemia may be involved, through adverse effects of potentially ‘toxic’ glucose
metabolites on the brain and its vasculature. Thirdly, insulin itself may be involved. Insulin can directly
modulate synaptic plasticity and learning and memory, and disturbances in insulin signalling pathways
in the periphery and in the brain have recently been implicated in Alzheimer’s disease and brain aging.
Insulin also regulates the metabolism of β-amyloid and tau, the building blocks of amyloid plaques and
neurofibrillary tangles, the neuropathological hallmarks of Alzheimer’s disease. In this paper, the evidence
for the association between DM2 and dementia and for each of these underlying mechanisms will be
reviewed, with emphasis on the role of insulin itself.
DM (diabetes mellitus) is associated with slowly progressive
end-organ damage in the brain [1]. Mild to moderate impairments of cognitive functioning has been reported both in
patients with DM1 (Type I DM) [2], and in patients with DM2
(Type II DM) [3,4]. Clinically relevant deficits, however,
mainly occur in elderly patients with DM2 [5], who may
experience problems with day-to-day functioning due to their
cognitive impairments [6]. The potential impact of DM on
cognition in the elderly is further emphasized by several large
epidemiological surveys that report an increased incidence
of dementia among DM patients, apparently concerning
both Alzheimer’s disease and vascular dementia [3,7–9]. The
observation that the effects of DM on the brain are most
pronounced in the elderly has been attributed to an interaction between DM and the normal aging process of the
brain [10,11]. Differences between the pathophysiology of
DM1 and DM2 are also likely to play a role [11], as the latter
is by far the most common form among the elderly. In DM1,
the principal defect is an autoimmune-mediated destruction
of pancreatic β-cells, leading to insulin deficiency, whereas
in DM2 the principal defect is insulin resistance, leading to
Key words: Alzheimer’s disease, brain aging, cognitive dysfunction, insulin-induced amyloid,
metabolic syndrome, Type II diabetes mellitus.
Abbreviations used: Aβ, β-amyloid; APOE, apolipoprotein E; DM, diabetes mellitus; DM1, Type I
DM; DM2, Type II DM; IDE, insulin-degrading enzyme; LDL, low-density lipoprotein; MRI, magnetic
resonance imaging.
1
To whom correspondence should be addressed, at Department of Neurology, G03.228,
University Medical Center Utrecht, PO Box 85500, 3508 GA Utrecht, The Netherlands
(email [email protected]).
On behalf of the Utrecht Diabetic Encephalopathy Study Group (see Acknowledgements)
2
a relative insulin deficiency. Moreover, DM2 occurs in the
context of a cluster of metabolic and vascular risk factors,
which is referred to as the so-called ‘metabolic syndrome’
[12]. The metabolic syndrome itself, with or without hyperglycaemia, is associated with atherosclerotic cardiovascular
disease, ischaemic stroke and with cognitive decline and
dementia [13]. A key question is therefore whether disturbances in insulin and glucose metabolism or other factors
from the metabolic syndrome lead to impaired cognition in
DM2. The present work aims to provide an overview on the
ways in which disturbances in glucose and insulin metabolism
and other factors related to the metabolic syndrome may
be implicated in the accelerated cognitive decline and the
increased risk of dementia in patients with DM2 (Figure 1).
Cognitive dysfunction and dementia in
DM2: underlying mechanisms
A role for hyperglycaemia?
Several lines of evidence suggest that ‘toxic’ effects of
hyperglycaemia are involved in the development of diabetic
end-organ damage to the brain [14]. Hyperglycaemic rodents,
for example, express cognitive impairments and functional
and structural alterations in the brain [14]. Toxic effects of
high glucose levels are mediated through an enhanced flux
of glucose through the so-called polyol and hexosamine pathways, disturbances of intracellular second messenger
pathways, an imbalance in the generation and scavenging
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Figure 1 Suggested pathogenesis of cognitive decline in DM2
Insulin resistance and risk factors related to the metabolic syndrome
lead to DM2. The adverse effects of the metabolic syndrome and DM2
a strong predictor of cognitive dysfunction in DM2, and if
this effect is (partially) independent of disturbances in glucose
and insulin metabolism.
on the brain are mediated through ischaemic cerebrovascular disease, in
concert with other factors from the metabolic syndrome. Hyperglycaemia
plays an additional role through ‘toxic’ effects on brain tissue and
Involvement of ischaemic cerebrovascular
disease?
the development of cerebral microangiopathy. Alterations in insulin
metabolism can also directly affect the brain, through involvement
in synaptic plasticity and amyloid and tau metabolism. Ischaemic
cerebrovascular disease plays a modulating role in these latter processes.
of reactive oxygen species, and by advanced glycation of
important functional and structural proteins [15]. These
processes directly affect brain tissue and lead to microvascular
changes in the brain [11,14].
Still, hyperglycaemia is unlikely to be the only factor in
the development of cognitive impairments in DM2: previous
studies in DM2 patients do not invariably show an association
between chronic hyperglycaemia, as assessed by HbA1 levels,
and the severity of cognitive impairments [3,10]. Moreover,
changes in cognition may already develop in ‘pre-diabetic
stages’, such as impaired glucose tolerance, or in newly
diagnosed DM2 patients that have not yet been exposed to
long-term hyperglycaemia [16,17].
A role for the metabolic syndrome?
DM2 and insulin resistance are closely associated with factors
such as obesity, atherogenic dyslipidaemia [elevated triacylglycerol level, small LDL (low-density lipoprotein) particles,
low HDL (high-density lipoprotein) cholesterol], raised
blood pressure, and pro-thrombotic and pro-inflammatory
states. Together these factors constitute the metabolic syndrome, or insulin resistance syndrome [12,18]. A number
of factors from this syndrome have been identified as
independent predictors of cerebrovascular disease, ischaemic
stroke and accelerated cognitive decline and dementia (e.g.
[13,16,19–21]). The combined occurrence of these risk
factors in the metabolic syndrome might reinforce these
effects [19,22–24]. Given the clustering of insulin resistance,
hypertension and dyslipidaemia in DM2 it may be difficult
to determine which factor is the prime determinant in the
development of cognitive dysfunction. The main question,
however, is to determine if the metabolic syndrome is indeed
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DM2 and the metabolic syndrome are risk factors for
atherosclerosis of the carotid and intracranial arteries [22,25],
thus increasing the risk of stroke, and of cognitive decline and
dementia [26]. In the long term, exposure to hyperglycaemia
in DM may lead to abnormalities in cerebral capillaries, such
as basement membrane thickening [27]. These microvascular
changes may also lead to chronic and insidious ischaemia of
the brain, thus contributing, for example, to the development
of subcortical white-matter lesions. On a population level
these lesions are associated with cognitive impairments,
particularly related to frontal lobe functions [28]. Although
white-matter lesions are also common among healthy elderly
subjects, their prevalence and severity is increased in patients
with vascular risk factors or ischaemic vascular disease, and
in demented patients [28]. MRI (magnetic resonance imaging)
studies in DM2 patients indeed show an increased severity of
white-matter lesions {[29], and S.M. Manschot et al., Utrecht
Diabetic Encephalopathy Study Group (see Acknowledgements), unpublished work}, and an increased incidence of
(silent) brain infarcts [30].
An interaction with aging?
As the effects of DM on the brain are most pronounced in
the elderly, one may suggest that the aging brain is more
susceptible to the effects of DM or that the effects of DM
and aging interact. In fact, several of the mechanisms that
are assumed to mediate the toxic effects of hyperglycaemia
on the brain, such as oxidative stress, the accumulation of
advanced glycation end-products and microangiopathy, are
also involved in brain aging [11]. Moreover, experimental
studies indicate that the behavioural and neurophysiological
consequences of DM are accentuated by aging [31]. We
are currently addressing this issue by comparing cognitive
functioning and brain MRI in aged DM1 and DM2 patients
with controls [32]. Our results suggest that the cognitive
impairments and MR changes are less marked in the aged
DM1 patients (average duration of DM ±35 years), than
in DM2 (average known duration of DM 9 years) patients
of similar age (A.M.A. Brands et al., Utrecht Diabetic
Encephalopathy Study Group, unpublished work). This
suggests that, in addition to age, differences in the pathophysiology of DM1 and DM2 are likely to be important
determinants of the effects of DM2 on the brain.
Direct effects of insulin on the brain?
An increasing amount of evidence links insulin itself to
cognitive decline and dementia in DM2 [33–35]. First, alterations in cerebral insulin receptor signalling may be involved,
as a cerebral equivalent of peripheral insulin resistance.
Secondly, insulin may affect the metabolism of Aβ (βamyloid) and tau, two proteins that represent the building
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blocks of amyloid plaques and neurofibrillary tangles, the
neuropathological hallmarks of Alzheimer’s disease.
Insulin is not a major regulator of glucose use in the brain,
in contrast with its prominent action in peripheral tissues
such as liver, muscle and fat [36]. Still, insulin and its receptor
are widely distributed throughout the brain, with particular
abundance in defined areas, such as the hypothalamus and the
hippocampus [37], and play a role in the regulation of food
intake and body weight [36]. In addition, insulin appears to
act as a ‘neuromodulator’. It influences the release and reuptake of neurotransmitters, and also appears to improve
learning and memory [37]. The initial components of the
insulin receptor signalling cascade in the brain are largely
similar to those of the periphery [37,38], but the downstream
targets of the cascade are quite different, probably involving,
among others, neuronal glutamate receptors [37].
Disturbances in cerebral insulin signalling pathways may
be involved in Alzheimer’s disease and brain aging [33–35].
Aging is associated with reductions in the level of insulin
and the number of its receptors in the brain [39]. In
Alzheimer’s disease this age-related reduction in cerebral
insulin levels appears to be accompanied by disturbances of
the insulin receptor signalling [39], leading to the qualification
of Alzheimer’s disease as ‘an insulin-resistant brain state’ [40].
The relation between insulin and the metabolism of Aβ
and tau is also receiving increasing attention [33,35]. Aβ is
derived from the so-called amyloid precursor protein. After
secretion into the extracellular space Aβ can aggregate with
other proteins, to form senile plaques. Alternatively, excessive
Aβ can be cleared through LDL-receptor-related protein mediated endocytosis, or through direct extracellular
proteolytic degradation [41]. This latter process involves IDE
(insulin-degrading enzyme) [42]. Insulin appears to stimulate
Aβ secretion, and inhibits the extracellular degradation of Aβ
by competition from IDE [33]. A recent histopathological
study of the hippocampus in patients with Alzheimer’s
disease reported marked reductions in IDE expression, and
IDE mRNA levels, relative to controls [43]. Interestingly,
this reduced expression only occurred in patients with the
APOE (apolipoprotein E) ε4 allele. An interaction with
the APOE ε4 genotype has also been demonstrated for the
risk of Alzheimer’s disease in DM patients [8], an observation
that was supported by neuropathological results [8].
Although the concepts of ‘cerebral insulin resistance’,
and ‘insulin-induced amyloid pathology’ are an attractive
explanation for some of the effects of DM2 on the brain,
there are still many loose ends. In contrast with the increasing
body of knowledge on the mechanisms of insulin resistance
in peripheral tissues [44], we know relatively little on how
DM2 and its treatment affect cerebral insulin and its receptor.
Moreover, the knowledge on the role of insulin in brain
physiology is far from complete. For example, in apparent
contrast with previous observations that hippocampal insulin
receptor expression and signalling in rats are up-regulated
following a spatial learning task in a water maze [45], mice
with a targeted knockout of insulin receptors in the brain
readily learn this same task [46]. Hopefully, ongoing research
in this rapidly evolving field of research will clarify these
issues.
Conclusion
Several mechanisms may be involved in accelerated cognitive
decline and the increase of dementia in patients with DM2
(Figure 1). Because these different mechanisms interact at
several levels, it is unlikely that future studies will detect a
single factor that link DM to impaired cognition. It may be
possible, however, to identify processes, or clusters of risk
factors, that explain at least part of the association, and can be
targeted by preventive measures. These preventive measures
may not only include improvement of glycaemic control [47], but could also be directed at vascular risk factors
and insulin metabolism. In fact, there is already some evidence
from studies in non-DM patients that these latter approaches
may be successful. For example, treatment of vascular risk
factors, such as hypertension, may decrease the incidence of
dementia in the context of ischaemic cerebrovascular disease
[48]. Moreover, a recent exploratory randomized placebocontrolled trial with the insulin-sensitizing compound rosiglitazone showed an amelioration of both cognitive decline
and abnormalities in cerebrospinal fluid Aβ in non-DM
patients with early Alzheimer’s disease [49]. The challenge for
future studies will be to determine what preventive strategy
should be applied in which DM2 patient, at what stage of the
disease.
The Utrecht Diabetic Encephalopathy Study Group consists of (in
alphabetical order): Department of Clinical Neurophysiology: A.C.
van Huffelen; Department of Internal Medicine: H.W. de Valk; Julius
Center for Health Sciences and Primary Care: A. Algra, G.E.H.M.
Rutten; Department of Medical Pharmacology: W.H. Gispen; Department of Neurology: A. Algra, G.J. Biessels, L.J. Kappelle, S.M.
Manschot, J. van Gijn; Department of Neuropsychology and
Helmholtz Research Institute: A.M.A. Brands, E.H.F. de Haan, R.P.C.
Kessels, E. van den Berg; Department of Radiology: J. van der Grond,
all part of the University Medical Center, Utrecht, The Netherlands.
The research of the Study Group is supported by the Dutch Diabetes
Research Foundation (grants 2001.00.023 and 2003.01.004).
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Received 20 June 2005